Compounds circulating in the bloodstream of vertebrates cannot freely diffuse into brain tissue due to the blood-brain barrier. This barrier is beneficial in protecting the brain from exogenous influences. However, this beneficial role can become detrimental in a situation requiring therapeutic intervention by a drug with a site of action in the brain, if that drug does not readily cross the blood-brain barrier. For instance, it may not be possible to administer a drug in high enough doses to elevate the systemic levels of the drug blood level sufficiently to achieve a brain blood level effective to produce a desired effect. This situation is particularly likely when the drug sought to be administered to the brain has toxic or unpleasant side effects to the remainder of the body. This problem is exacerbated if the condition requiring therapy is associated with a reduction in blood flow through the brain, such as that occurring due to an ischemic stroke or a cardiovascular event resulting in loss of blood pressure or restricted blood flow to the brain.
Stroke, which is often cited as the third most frequent cause of death in the developed countries, has been defined as the abrupt impairment of brain function caused by a variety of pathologic changes involving one or several intracranial or extracranial blood vessels. Approximately 80% of all strokes are ischemic strokes, resulting from restricted blood flow. Thus, patients afflicted with stroke may especially benefit from increased blood flow and enhanced delivery of anti-stroke and/or neuroprotectant drugs.
Excitotoxic and apoptotic mechanisms have been implicated in the pathophysiology of cerebral ischaemia. MK-801, a glutamate antagonist (non-competitive NMDA channel blocker), protects rat brain from ischaemic cell damage and is the prototype of neuroprotective drugs which enhance resistance to ischemic injury. Neuroprotectants have failed in clinical trials, in part because adequate blood (brain) levels could not be achieved or because of toxicity.
Consequently, reductions in the level of cerebral blood flow may be a significant factor in the uptake of drugs particularly lipophilic drugs, such as MK-801, into brain tissue. Under conditions of ischemia and severely reduced blood flow, the uptake of such drugs is found to be severely reduced. In particular, the potential for achieving therapeutically relevant brain levels of neuroprotective drugs is likely to be severely reduced under circumstances of stroke. Therefore the ability to increase cerebral blood flow and enhance drug delivery, especially under stroke conditions, is highly desirable.
It is an object of this invention to provide a method for increasing cerebral bioavailability of drugs.
It is an object of this invention to provide a method for increasing cerebral bioavailability of drugs in response to increased cerebral blood flow.
Nitric oxide has been shown to be a vasodilator for the peripheral vasculature in normal tissue of the body. Surprisingly, the present inventors have determined that increasing NO levels via generation of nitric oxide by endothelial nitric oxide synthase (eNOS) and/or non-ecNOS dependent mechanisms also affects the vasculature in brain tissue, causing vasodilation without loss of blood pressure. As a result, release of nitric oxide in the brain vessels causes an increase in blood flow through brain tissue which is not dependent on increases in blood pressure. The present invention uses the blood-pressure-independent increase in blood flow through brain tissue to increase cerebral bioavailability of blood-born compositions.
The present invention provides for increased cerebral bioavailability of blood-born compositions by administering the composition of interest while increasing brain NO levels. This increase in NO levels may be accomplished by stimulating increased production of NO by eNOS, especially by administering L-arginine, by administering agents that increase NO levels independent of ecNOS, or by any combination of these methods. As NO is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue. By increased flow, the site of action will be exposed to more drug molecules. By stimulating increased NO production, administration of drugs that are not easily introduced to the brain may be facilitated and/or the serum concentration necessary to achieve desired physiologic effects may be reduced.
In an important embodiment, the present invention provides for enhanced delivery of drugs to brain tissue by administering the drug of interest (also called the xe2x80x9csecond agentxe2x80x9d or xe2x80x9cphysiologically active composition (or agent)xe2x80x9d) while increasing brain NO levels. This increase in NO levels may be accomplished by stimulating increased production of NO by eNOS, especially by administering L-arginine, by administering agents that increase NO levels independent of ecNOS, or by administering any combination of these agents. Preferably, these agents are administered in amounts effective to increase NO levels and/or cerebral blood flow. As NO is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue. By increased flow, the site of action will be exposed to more drug molecules. By stimulating increased NO production, administration of drugs that are not easily introduced to the brain may be facilitated and/or the serum concentration necessary to achieve desired physiologic effects may be reduced.
In one preferred embodiment, this invention provides a method to enhance delivery of a desired composition to brain tissue of an individual comprising introducing the composition into the blood stream of the individual substantially contemporaneously with a blood flow enhancing amount of L-arginine.
In another preferred embodiment, this invention provides a method to enhance delivery of a desired composition to brain tissue of an individual comprising introducing the composition into the blood stream of the individual substantially contemporaneously with a blood flow enhancing amount of L-arginine and/or a blood flow-enhancing amount of a non-ecNOS NO-generating system.
Preferably, agents such as HMG-CoA reductase inhibitors, rho-GTPase inhibitors, and inhibitors of actin cytoskeletal organization are not administered in the methods according to the present invention and are not included in the compositions according to the present invention. Also, preferably, protein kinase C inhibitors, and isoquinolinesulfonyl compounds or their derivatives, including but not limited to H-7 and H-8 are not administered in the methods according to the present invention and are not included in the compositions according to the present invention. In certain embodiments, cyclosporin-A (Cs-A) is not administered in the methods according to the present invention and is not included in the compositions according to the present invention.